Salivary gland dysfunction affects millions of Americans whose quality of life is severely impacted by dry mouth, oral bacterial infections, poor nutrition, and other disorders that are associated with decreased saliva production. Loss of saliva production is most common in Sjgren's syndrome (SS), an autoimmune exocrinopathy of unknown etiology in which decreased saliva production is followed by lymphocytic infiltration of the salivary gland and ultimately tissue degeneration. In addition, salivary gland inflammation and hyposalivation is an unintended side effect of ?-radiation used for the treatment of head and neck cancers. Understanding the mechanisms underlying early events in salivary gland inflammation will help identify currently-unavailable therapeutic options to treat salivary gland degeneration. It is now well recognized that high levels of intracellular nucleotides, particularly ATP, are released from cells under pathological conditions in response to inflammation, stress or trauma. Our research has focused on understanding the ATP- dependent mechanisms involved in salivary gland inflammation and degeneration. Recent work by our group indicates that salivary gland inflammation can be initiated by activation of the P2X7 receptor (P2X7R), an ATP- gated, non-selective cation channel that also promotes inflammation and cell apoptosis in several chronic diseases, including rheumatoid arthritis, lung fibrosis, and neurodegenerative and inflammatory bowel diseases. Preliminary studies presented in this proposal indicate that neutrophil recruitment to duct-ligated submandibular gland (SMG) is significantly reduced in P2X7R-/- mice compared to control mice when the glands were perfused with BzATP, a high affinity P2X7R ligand that we initially developed. Therefore, we will utilize primary isolated salivary gland cells and the duct ligation model of salivary gland inflammation in wild type and P2X7R-/- mice to elucidate whether inflammatory responses associated with the P2X7R play a significant role in functional SMG degeneration and the mechanisms involved (Specific Aim 1). Other studies will extend these results to mouse models of radiation-induced salivary gland damage (Specific Aim 2) and autoimmune exocrinopathy (Specific Aim 3), where the availability of the P2X7R-/- mouse and P2X7R-selective antagonists (currently in clinical trials for the treatment of rheumatoid arthritis and spinal cord injury) will enable us to directly examine whether decreases in P2X7R function in vivo can retard salivary gland degeneration. Thus, the overall goal of these studies is to evaluate whether inhibition of P2X7R activity can protect the salivary gland from various forms of tissue damage in mice, which ultimately will be essential for developing treatments for human salivary dysfunction.